Piperidino tertiary amino alcohols



United States 6 Claims. (Cl. 260294.7)

The present invention is concerned with a novel group of synthetic,physiologically active basic tertiary alcohols, their acid addition andquaternary salts. As such, the present application constitutes acontinuation-in-part of my copending application for United StatesLetters Patent, Serial No. 691,881, filed August 20, 1946.

Many different synthetic compounds, pharmacologically active asanti-spasmodics and local anesthetics, have been synthesized from timeto time. The more active and apparently useful of these compounds havein general comprised fairly complex molecules containing at least oneester grouping. This grouping was generally accepted as being essentialon the basis of analogy to the naturally occurring extractives whichwere considered esters of tropic or pseudo-tropic acids.

Unfortunately, for one reason or another, many if not most of thesecompounds were not wholly satisfactory. Among other factors, thepresence of the ester grouping introduces a chemically labile structurewhich adds to the instability of the molecule. This instability createsdilriculty in the laboratory, making the preparation, purification, andhandling of the materials extremely difficult. Further, modification mayoccur in several ways in the animal organism in which the compound isattempted to be used. For example, the compound may break down intoother compounds which are ineffectual, or which are irritating, or whichmay even be highly toxic.

It is, therefore, the principal object of the present invention todevelop a series of compounds which are physiologically active,especially as anti-spasmodics. In so doing, it is a further and addedobject to develop materials which are not subject to the objectionablebreakdown which so frequently characterized the more active of thepreviously-known synthetic, pharmacologically active esters.

In the accomplishment of these objects in accordance with the presentinvention the surprising fact has been found that the ester grouping,previously considered essential in the prior art, is quite unnecessary.It has been found in'accordancewith the present invention that thedesirable characteristics are evidenced by a group of basic nitrogenoustertiary alcohols containing no ester group- H In general, the objectsof the present invention have been accomplished in the development andsynthesis of basic tertiary alcohols of the general formula.

Alk wherein the groupings designated R, Alk, and Het represent variedsubstituents as defined immediately below.

R and Alk, by their location on the molecule, may be considered asinterchangeable. In the instant application, R, for example, willusually be a phenyl, naphthyl, furyl or thienyl radical, or a monoordilower alkyl, hydroxy, alkoxy, chloroor bromo-substituted phenyl ornaphthyl radical. saturated or unsaturated aliphatic radical of aboutl-12 carbon atoms. The group designated as Het may be the l-piperidylradical. v

v From the foregoing description, it will be seen that compounds inaccordance with the present invention may vary quite widely in scope andstructure. Typical illustrative compounds within the specificlimitations of this Alk, as shown in the formula, will represent a atentO 2,723,269 Patented Nov. 8, 1955 formula are shown in the followingtable, in which the compounds are indicated by the values of R, Alk, andHet, in the formula given above.

TABLE r Het l-piperidyl.

Z-naphthyl 4ch1oro-1-naphthy1 Do Z-furyl 4-hydroxyphenyl z-chlorophenylBA-dimethylphenyl 3,4-d1methoxyphenyl. 3,4-dihydroxyphenyl2,4-dimethylphenyl 3,4-dich1orophenyL. 2, fi-dimethylphenyl In general,the basic tertiary alcohols of the present invention comprisecrystalline solids, usually having a sharp melting point, although someare inclined to sinter slightly just below the melting point. Some ofthe compounds, however, are so difficultly crystallizable as to appearto be permanent oils and some few appear actually to be permanent oils.The crystalline compounds appear to be free from color when pure. Mostof the alcohols are relatively insoluble in water but are readilysoluble in ether and in alcohol-ether mixtures.

The alcohols readily form crystalline addition salts, such ashydrochloride, nitrate, citrate and the like, by reacting the alcohol insolution with the desired acid in the usual way. The hydrochlorides, forexample, are readily formed and are soluble in aqueous solution. In somecases the water-solubility is so marked that the salts are extremelyhygroscopic and in crystalline form must be carefully handled; Theypossess the markedly useful property in aqueous solution of remainingstable over long periods of time. Quaternary salts, such'as themethobromide, methiodide, ethiodide, and the like, are

also readily formed and have a number of desirable properties. Severalof them also possess desirable mydriatic properties. The acid additionand quaternary salts, therefore, possess marked utility forpharmacological experiment.

It is surprising that the basic tertiary alcohols of this inventionshould possess anti-spasmodic properties, in view of the previouslyconsidered desirability of the ester grouping. Especially is this asurprising feature in view of the fact that secondary alcohols ofsimilar structure, for example 3-(l-piperidyl)-1-phenyl-1-propanol andthe like, also possess no appreciable pharmacological activity asspasmolytics.

It is still more surprising, in view of the fact that very closelyanalogous basic tertiary alcohols possess no pharmacological utility inthis respect. For example, compounds in which both R and Alk are alkylradicals have relatively little or no useful anti-spasmodic activity,and compounds in which both R and Alk are alkyl radicals, and Het isreplaced by a dialkylamino radical,

v have no anti-spasmodic activity.

The basic tertiary alcohols of this invention appear to be activeagainst both musculotropic and neurotropic spasm, being particularlyeffective against the latter. In addition to their surprisingly greatactivity, the compounds are, in general, characterized by a remarkablylow toxicity. Considering the product of these two factors of activityand toxicity as a pharmacological index, many of the compounds are,therefore, considerably more useful than either atropin or Trasentin.

In addition, the compounds vary as to the rate of onset and as toduration of activity. It is, therefore, possible to select a compoundfrom the series suitable for almost any anti-spasmodic'purpose. Theirutility is, therefore, possible in a wide variety of fields.

Secondary alcohols, such as those previously noted, were prepared bycatalytic hydrogenation of the corresponding ketone. The new basictertiary alcohols of the present invention, being of entirely differenttype, cannot be prepared in the same way. It was found, however, that byjudicious selection of reactants, the compounds of the present inventioncan be readily synthesized.

Perhaps the most satisfactory way was found to be the addition of asuitable Grignard reagent to the proper basic ketone in the presence ofa suitable solvent for both. Heating for sufficient time to complete thereaction, followed by hydrolysis, produces the desired basic tertiaryalcohol. A typical illustration of the reaction may be indicated asfollows:

R OMgBr AlkMgBr \& R-COOHaCHz-Eot+ -CH2CHzHet Alk R OH I H2O CCH2-CH2HetAlk Since the first stage in this reaction must be carried out parentlytends to form an insoluble-complex with the ketone.

In such cases, the chloride appears to produce the least insolublecomplexes and, therefore, may be preferable. For a similar reason, insuch cases the use of a higher boiling solvent, such as dibutyl ether,may become preferable in order to utilize increased temperature andthereby improve the solubility.

The amount ofGrignard reagent chosen also has an effect on the yield.Apparently, this again may be due to the formation of a complex. Thelatter is believed to form but to break down on hydrolysis. For thisreason, it appears that some of the reagent is not available for furtherreaction. in any case, a-considerable increase over an equimolecularamount of the Grignard reagent ordinarily produces a definitelyincreased yield. Above about two molecular equivalents, however, furtherincrease in the amount used produces a markedly diminishing return.About two moles of Grignard reagent per mole of ketone appears to be thepreferable range.

The invention will be illustrated in conjunction with the followingexamples, which are to be taken as illustrative only and not by way oflimitation. All parts are by weight, unless otherwise noted.

Example 1.I-(1-piperidyl)-3-phenyl-3-heptan0l To a chilled ethersolution of n-butylmagnesium bromide (prepared from 274 parts n-butylbromide, 48.6 parts magnesium turnings, and 800 parts by volume absoluteethyl ether) is added, with stirring, over a period of 25 minutes, a drysolution of 217 parts omega-(lpiperidyl)-propiophenone in 800 parts byvolume of ether. The resulting reaction mixture is stirred for about 1hour and allowed to stand at room temperature until reactionsubstantially ceases. The reacted mixture is chilled in an ice bathWhile it is slowly treated with 600 parts by volume of 5 N hydrochloricacid. The solid formed is collected on a filter, air-dried, redissolvedin 2500 parts of water at C., the solution is treated with decolorizingcharcoal and clarified by filtration. The filtrate is chilled until itstarts to become cloudy and is then made alkaline with ammonia. Thesolid which precipitates is collected on a filter as crudel-(l-piperidyl)-3-phenyl-3-heptanol and purified by recrystallizationfrom dilute alcohol; when pure it melts at 5656.7 C. (uncorrected) withpreliminary softening at 54.4 C. It forms a hydrochloride which melts at223-224 C. (uncorrected) with some decomposition.

By following the procedure of the above example, but by using anequivalent amount of an alkylmagnesium halide, prepared from an alkylhalide in column 1 of Table II (below) instead of n-butylmagnesiumbromide, the corresponding piperidyl tertiary alcorols listed in column2 of Table II are obtained. Column 3 lists the melting points of thepiperidyl tertiary alcohol, while column 4 lists the melting points oftheir hydrochlorides.

TABLE II y r0- Alkyl Hallde Piperldyl Tertiary Alcohol M. P., C.chloride,

methyl chloride 4-(l-piperidyl)-2-phenyl-2-butanol 1 137-142/3 mm. 200.3-200. 9 ethyl bromide l-(l-piperidyl)-3-phenyl-3-peuta- 82.5-83.0 185.0-1855 n n-propyl chloride l-(l-lpiperidyl)-3-phenyl-3-hexa- 92.2-94.0202. 0-203. 5

no isopropy1chloride 1-(l-piperidyl)-3-phenyl-4-methyl- 72.7-75.1 2

3-pentanol. allyl chloride 6-(1-t1 iperidyl)-4-phenyl-1-hexen- 180.5-1829 4-0 isobutyl bromide -glgnperidyl)-3-pheny1-5-methyl- 53.1-56.6218. 2-219. 7

exano sec.-butyl bromide 1-glipiperidyl)-3-pheny1=4-methyl- 210. 0-212.5

exano tert.-butyl ch1oride- 1 (1-piperidyI)-3-pheny1-4,4-di- 228. 5-230.0

, methyl-B-pcntanol. n-amyl bromide 1-(l-piperidyl)-3-phenyl-3-octanol63.5-65.5 200. 0-204. 5 isoamyl bromide 1'-glgnptsridil)-3-phenyl-6-methyl- 59.0-59.5 '240.0-?A0.'5

an arm n-heptyl bromide" l-(l-piperidyl)3-phenyl-3-decanol 63.0-65 5207. 0-209. 5 n-duodecyl bromid l-(dl-pipesidyl)-3-phenyl-3-penta- 192.0-193. 5

ecano Boiling point instead of melting point. Melts in approx mately 10seconds when immersed in bath at 175 C.

By following the procedure of Example 1, but by using 1 an equivalentamount of ethylmagnesium bromide instead of n-butylmagnesium bromide,and by using an equivalent amount ofbeta-[2-(1,2,3,4-tetrahydroisoquinolyl)]- propiophenone instead ofbeta-(1-piperidyl)propiophenone, the above pentanol is obtained. Whenpurified by recrystallization, from dilute alcohol, it melts at92.2-93.1 C. Its hydrochloride, prepared and purified in the usual way,melts at 202.2-203.0 C.

In the above procedure, if an equivalent amount of the propiophenonesand propionaphthoneslisted in column l'of Table III (below) are usedinstead of beta-[2- (1,2,3,4-tetrahydroisoquiuolyl)]propiophenone, thecorresponding pentanols listed in column 2 are obtained. Column 3 liststhe melting points of their hydrochloric'les.

Example 3.1-(4-morph0linyl) -3- (Z-naphthyl) -3- heptanol By followingthe procedure of Example 1, but by using an equivalent amount ofbeta-(4-morpholinyl)-2-propionaphthone instead ofbeta-(1-piperidyl)propiophenone,1-(4-morpholinyl)-3-(2-naphthyl)-3-heptanol is obtained. Itshydrochloride, prepared and purified in the usual way, melts at220.5-221.0 C. with decomposition.

In the above procedure, if an equivalent amount of the propiophenonesand propionaphthones listed in column 1 of Table IV (below) are usedinstead of beta-(4- morpholinyl) 2 -propionaphthone, the correspondingheptanols listed in column 2 are obtained. Column 3 lists the meltingpoints of the hydrochlorides of the heptanols.

TABLE IV Basie Ketone Heptanol Beta (1 piperidyl) 4 chlor 1- o- Beta (4morpholinyl) 4-chloro-1-.

1- (1 -piperidyl) -3- (4-bromophenyl)-3-heptanol.

l (1- piperidyl) 3 (4 -ethylphenyl)-3-heptanol.

1 (1 piperidyl) -3 (2-naphthyll-3-heptanol.

1- (1-piperidyl) -3- (t-chloro- 1-naphthyD-3-heptanol.

1 (4 morpholinyl) 3 (4 chloro-l-naphthyl) -3-heptanol.

As noted above, the compounds of the present invention possess utilityas anti-spasmodics. An indication of their efifectiveness may beobtained by the commonlyused test of ability to relax isolated rabbitintestinal strips which are immersed in a constant temperature testsolution. In the following Table V, illustrative results are shown. Inthe tests shown, spasticity was induced by furfuryl trimethyl ammoniumiodide in 0.1 mgm./ ml. of Tyrodes solution.- In the table, if thespasticity was counteracted to the extent that the gut assumed normalactivity, relaxation is said to be 100%. If the gut shows essentially nocounteractions afterthe anti-spasmodic drug, the condition is recordedas complete relaxation. The test compounds have the formula TABLE VPercent Relaxation (Average Number of Tests) Compound R 39 comp.

5 64 comp. 79 100 comp. 1 100 comp. comp. comp. comp. comp.

Trasentin ethyl n-propyl n-butyl 1 Dose, mgmJlOO cc. I Completerelaxation in several tests.

The adverse effect on the anti-spasmodic activity of the propanols ofthe present invention is shown in the following Table VI. The testresults show the extremely poor quality of the product obtained when Rin the general formula is an alkyl radical such as ethyl, and also thelack of activity when both R and Alk represent alkyl radicals and Het isreplaced by a dialkylamino group.

TABLE VI Percent Relaxation of Spastic Gut Compound OH 0CH2CH2N\ H 0 564 comp. comp. C2115 I C211 OH O0 H2CH2N H 0 0 0 0 50 CzHs CH3 OH /CHaCCH2'CH2-N 0 0 0 0 0 CH3 CH3 1 Dose, mgm./ 100 cc.

The compounds of the present invention are also effective against bariumchloride spasm. Illustrative results of testing efiectiveness incounteracting spasticity insalts thereof.

I claim: 1. A compound of the group consisting of tertiary aminoalcoholsof the formula 1-( l-piperidyl -3 -phenyl-3 -heptanol.

l-( 1-piperidyl)-3-phenyl-3 -pentan0l. 1-(1-piperidyl)-3-phenyl-3-hexano1.

l-( 1-piperidyl)-3 -phenyl-4-methyl-3 -pentanol. 1-( l-piperidyl) -3-phenyl-6-methyl-3 -heptanol.

References Cited in the file of this patent UNITED STATES PATENTSFourneau Aug. 14, Klarrer Oct. 30, Miescher et a1. Nov. 26,

FOREIGN PATENTS Switzerland 2. Feb. 16, France Feb. 3,

OTHER REFERENCES H OH CHz-CH2 GOH2CH2N 0111 (1938) pp. 1372-76. AlkCH2-C2 wherein R is a member of the group consisting of phenyl andnaphthyl and AIR is a lower alkyl and acid addition Trefuel et al.:Chem. Abst, vol. 24 (1930) p. 3502 Mannich et a1: Chem. Abst., vol 22(1928) pp. 590- Campbell et al.: Jour. Amer. Chem. Soc., vol. 60

Marie: Bull. Soc. Chem. (4) 3 (1908) pp. 280-86.

